The invention relates in general to substituted metallic complexes and more particularly to substituted porphyrin-, porphyrazine-, texaphyrin-, salen-, or corrole-metal complexes.
The peroxynitrite ion (ONOOxe2x88x92) is a potent oxidant formed by the combination of nitric oxide (NO) and the superoxide anion (O2)xe2x88x92. NO has been shown to be generated by numerous cell types, such as macrophages, neutrophils, hepatocytes and endothelial cells. The direct combination of NO with O2 produces the peroxynitrite ion (ONOOxe2x88x92), which decomposes rapidly under physiological conditions to oxidizing intermediates. These oxidizing intermediates can damage biological targets.
Pathological consequences associated with damage to biological targets can include the oxidizing or nitrating of proteins, lipids and DNA. ONOOxe2x88x92 crosses lipid membranes at a rate significantly faster than the rates of other known oxidants, indicating that this oxidant can travel distances of cellular dimensions. Thus, even in the presence of biological membranes, ONOOxe2x88x92 can have free access to cellular interiors. ONOOxe2x88x92 is also known to nitrate tyrosine residues in proteins, and to oxidize sulfhydryls, methionines and macromolecules such as, for example, metalloenzymes, DNA, and lipids.
In light of this reactivity, ONOOxe2x88x92 has been implicated in a variety of diseases. These diseases include, e.g., neurodegenerative disorders such as Alzheimer""s disease, amyotrophic lateral sclerosis, stroke, AIDS dementia and Hungington""s disease; heart diseases such as atherosclerosis; chronic inflammation and autoimmune diseases such as arthritis, inflammatory bowel disease, and acute respiratory disease syndrome; cancer; ischemia-reperfusion injury; septic shock; and chronic rejection of renal grafts.
The invention is based in part on the discovery of novel substituted metallic complexes that are effective peroxynitrite decomposition catalysts. Preferred catalysts have one or more of the properties of high catalytic activity, high stability and enhanced lifetime in the blood pool, advantageous tissue distribution, and low toxicity. The peroxynitrite decomposition catalysts can be used to treat a variety of conditions and diseases, including those known to involve the accumulation of the oxidant peroxynitrite.
Accordingly, in one aspect the invention provides a novel substituted metallic complex falling within one of formulas I through VII, as set forth in the Detailed Description of the Invention below. Compounds falling within the formula include various substituents, e.g., those including one or more polyethylene glycol (PEG) moieties.
Also provided are methods of treating neurodegenerative disorders, including Alzheimer""s disease, amyotrophic lateral sclerosis, stroke, AIDS dementia and Hungington""s disease; atherosclerosis; chronic inflammation; autoimmune diseases, including arthritis, inflammatory bowel disease, and acute respiratory disease syndrome; cancer; ischemia-reperfusion injury; septic shock; and chronic rejection of renal grafts in mammals by administering to a mammal in need of such treatment a pharmaceutically effective amount of a compound according to one of formulas I-VII.
In a further aspect, the invention also includes a method for the production of compounds according to any one of formulas I-VII.
Also provided are pharmaceutical compounds including the compounds of the invention and a pharmaceutically acceptable carrier.
In yet another aspect, the invention includes the use of compounds disclosed herein as diagnostic probes to determine the involvement of peroxynitrite and other reactive oxygen and nitrogen species in disease states both in vivo and in vitro.
The details of one or more embodiments of the invention are set forth in the accompanying description below. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the invention, the preferred methods and materials are now described. Other features, objects, and advantages of the invention will be apparent from the description and from the claims. In the specification and the appended claims, the singular forms also include the plural unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications cited in this specification are incorporated by reference.